Poly (ADP-ribose) Polymerase Inhibitors in Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled Trials

Context: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to standard-of-care (SOC) treatment (enzalutamide, abiraterone, or docetaxel) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is a limited integrated analysis of high-quality evidence comparing the efficacy and safety of PARPi and SOC treatments in this context. Objective: This study aims to comprehensively analyze the survival benefits and adverse events associated with PARPi and SOC treatments through a head-to-head meta-analysis in mCRPC. Evidence acquisition: A systematic review search was conducted in PubMed, Embase, Clinical trials, and the Central Cochrane Registry in July 2023. RCTs were assessed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review was prospectively registered on PROSPERO (CRD42023441034). Evidence synthesis: A total of 8 studies, encompassing 2341 cases in the PARPi treatment arm and 1810 cases in the controlled arm, were included in the qualitative synthesis. The hazard ratio (HR) for radiographic progression-free survival (rPFS) and overall survival (OS) were 0.74 (95% CI, 0.61–0.90) and 0.89 (95% CI, 0.80–0.99), respectively, in the intention-to-treatment patients. For subgroup analysis, HRs for rPFS and OS in the BRCA-mutated subgroup were 0.39 (95% CI, 0.28–0.55) and 0.62 (95% CI, 0.38–0.99), while in the HRR-mutated subgroup, HR for rPFS was 0.57 (95% CI, 0.48–0.69) and for OS was 0.77 (95% CI, 0.64–0.93). The odds ratio (OR) for all grades of adverse events (AEs) and AEs with severity of at least grade 3 were 3.86 (95% CI, 2.53–5.90) and 2.30 (95% CI, 1.63–3.26), respectively. Conclusions: PARP inhibitors demonstrate greater effectiveness than SOC treatments in HRR/BRCA-positive patients with mCRPC. Further research is required to explore ways to reduce adverse event rates and investigate the efficacy of HRR/BRCA-negative patients.


Introduction
A significant proportion of patients inevitably progress to a state of metastatic castration resistance, which represents the terminal clinical phase in the intricate trajectory of prostate cancer evolution.In such cases, the standard-of-care (SOC) treatment options commonly employed include chemotherapy, with docetaxel or cabazitaxel, and secondgeneration antihormonal therapy, encompassing abiraterone or enzalutamide [1,2].However, the meager survival benefits provided by these current therapeutic strategies have Medicina 2023, 59, 2198 2 of 17 spurred an intensified exploration for alternative or combinatorial drugs, ranging from radiotherapy to immunotherapy and microbiota-targeted therapy [1,3,4].Nevertheless, it is disheartening to note that these endeavors have not succeeded in significantly improving overall survival outcomes for patients with mCRPC [1,3,5].
Recently, the success of PARP inhibitors in other solid tumors has sparked interest in their potential application in mCRPC treatment, leading to multiple RCTs comparing PARP inhibitors with SOC treatment [6][7][8][9].As mutations of homologous recombination repair (HRR) genes (e.g., BRCA1/2) are found in approximately one-quarter of cases of mCRPC, multiple randomized clinical trials have been conducted to explore the efficacy and safety of PARP inhibitors compared to SOC treatments [10][11][12][13][14][15][16][17][18][19][20][21][22].Notably, due to the relatively better survival benefits observed in patients with BRCA1/2/ATM alterations in the treatment arm of the PROfound trial, olaparib has been approved and recommended for those with HRR gene alterations who have progressed to mCRPC after receiving previous next-generation hormonal drug treatment [13].In addition, other PARP inhibitors, such as talazoparib, niraparib, veliparib, and rucaparib, have also been tested in clinical trials for mCRPC and have reported encouraging data on the therapeutic performance of PARP inhibitors in terms of survival, further demonstrating the tremendous potential and necessity to use them in treating this lethal malignancy [12,17,18,20].
Despite having similar strict inclusion criteria, these high-quality randomized controlled trials (RCTs) have displayed inconsistent results regarding survival benefits and adverse events, partly due to disparities in participant numbers, HRR gene mutation status, treatment durations, and other factors.For instance, KEYLYNK-010 reported limited survival benefits and an unfavorable side effect profile of the treatment arm with a PARP inhibitor, while TRITON3 showed advantageous radiographic progression-free survival (rPFS) over the SOC arm and comparable rates of grade 3 or higher adverse events [19,20].Moreover, although similar improvements in rPFS were observed for patients with BRCA1/2 alterations in all RCTs, it remains controversial whether PARP inhibitors can be applied to mCRPC in patients without BRCA or even HRR gene mutations, despite recent evidence of novel mechanisms beyond inhibition of DNA repair in tumor cells [17,23].
Therefore, we performed this systematic review and meta-analysis to integrate all updated high-quality RCTs, aimed at analyzing primary endpoints and adverse events and exploring the efficacy of PARP inhibitors among specific patient subgroups.By synthesizing and integrating the available evidence, we hope that this study will provide guidance for defining the appropriate scope of PARP inhibitor application and support clinicians in making informed decisions regarding treatment options for mCRPC.

Search Strategy and Data Extraction
The review protocol was registered on PROSPERO (CRD42023441034) and conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines [24].PubMed, Embase, Clinical trials, and the Central Cochrane Registry were searched for RCTs using PARP inhibitors to treat mCRPC and published before 15 July 2023.The search keywords were as follows: ("PARP" OR "PARP inhibitors" OR "Olaparib" OR "talazoparib" OR "rucaparib" OR "niraparib" OR "veliparib") AND ("mCRPC" OR "metastatic castration-resistant prostate cancer").Next, two independent reviewers performed a literature screening.Of note, 4 publications of RCTs belong to the same study PROfound (NCT02987543), and two publications of RCTs belong to the same study with clinical trial number NCT01972217.We carefully compared all the publications affiliated with the same RCT and used the most updated and complete data.

Inclusion and Exclusion Criteria
The following studies were included: (1) randomized controlled trials; (2) patients with histologically or cytologically diagnosed mCRPC; (3) studies exploring the comparison between PARPi and SOC; (4) SOC treatment group studied was novel hormonal agents (NHA); (5) studies reported data on rPFS or OS.

Measure of Effect
OS and rPFS assessed by a blinded independent central review were the primary endpoints of interest.Other endpoints included in this meta-analysis were time to first subsequent therapy (TFST), time to PSA progression (TTPP), PSA response rate (a confirmed PSA decrease of at least 50%, PSA RR), and objective response rate (ORR).For safety analysis, rates of all grades, ≥3 grades, and serious treatment-emergent adverse events (AEs) were analyzed (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03).The key results of the meta-analyses are summarized in Supplementary Table S1.

Risk of Bias Assessment
The risk of bias for individual nonrandomized studies was analyzed in accordance with Cochrane recommendations using RevMan 5.3 by two independent reviewers.Studies with a significant risk of bias were excluded from the quantitative synthesis.

Statistical Analysis
We performed a meta-analysis of the mCRPC studies.The hazard ratio (HR) was calculated to evaluate the OS, rPFS, and TFST.The odds ratio (OR) was estimated to evaluate the PSA response and ORR, as well as AEs.All estimates were expressed with their 95% confidence intervals (CIs).On this basis, we divided the patients into four subgroups according to their HRR and BRCA mutation status to discuss whether the different mutation statuses would have different outcomes in terms of efficacy benefit.All meta-analyses were performed using a random-effects model and produced into forest plots using Cochrane Collaboration ReviewManager software (RevMan 5.3).We used R 4.2.3 to conduct a sensitivity analysis by eliminating one by one method to evaluate the consistency of the results.p < 0.05 (two-tailed) was considered statistically significant, and I 2 > 50% was defined as high heterogeneity.

Study Selection
The initial search identified 1476 publications, and a total of 1225 publications remained after the elimination of the duplicates.Then, 1147 articles were excluded after screening the titles and abstracts, and full-text reviews were performed on 78 articles.According to the selection criteria, we filtered eight studies comprising 4151 patients for inclusion in this meta-analysis.The entire process of initial screening and the reasons for excluding studies are illustrated in Figure 1.The characteristics of the included studies and patients are shown in Tables 1 and 2. All these studies were published between 2018 and 2023, and were multicenter, prospective, large-scale clinical RCTs.Each risk of bias for the included studies was analyzed using RevMan 5.3 according to Cochrane recommendations, and the methodological quality of most studies was deemed good (Figures S1 and S2).

rPFS
This meta-analysis was conducted on trials reporting rPFS as the primary endpoint and not differentiating between mutation status.The results showed that the PARPi treatment demonstrated superior efficacy (HR, 0.74; 95% CI, 0.61-0.90)compared to the control treatment (Figure 2A).Sensitivity analyses were performed, and the results showed good concordance between the trials (Figure S3A).

rPFS
This meta-analysis was conducted on trials reporting rPFS as the primary endpoint and not differentiating between mutation status.The results showed that the PARPi treatment demonstrated superior efficacy (HR, 0.74; 95% CI, 0.61-0.90)compared to the control treatment (Figure 2A).Sensitivity analyses were performed, and the results showed good concordance between the trials (Figure S3A).A similar favorable result for PARPi was obtained among patients with HRR gene mutations (HR, 0.57; 95% CI, 0.48-0.69),while no significant advantage of PARPi over standard therapy was demonstrated (HR, 0.85; 95% CI, 0.63-1.14) in populations without detectable HRR gene mutations (Figure 2B,C).
Notably, sensitivity analysis showed that even after excluding KEYLYNK-010, PARPi still exhibited improved efficacy in patients without HRR gene alterations (HR, 0.74; 95% CI, 0.62-0.88),underscoring the need for further exploration of PARPi efficacy in a wider range of patients (Figure S3B).

OS
OS was considered a secondary outcome in the studies included in this meta-analysis.For the overall patient population, even though individual trials had negative results, a conservative model was used to derive a slight benefit for PARPi treatment compared to NHA (HR, 0.89; 95% CI, 0.80-0.99)(Figure 3A).Considering the very low heterogeneity of the original study, which became statistically significant after meta-analysis with a larger sample size (Figure S3E).
Notably, sensitivity analysis showed that even after excluding KEYLYNK-010, PARPi still exhibited improved efficacy in patients without HRR gene alterations (HR, 0.74; 95% CI, 0.62-0.88),underscoring the need for further exploration of PARPi efficacy in a wider range of patients (Figure S3B).

OS
OS was considered a secondary outcome in the studies included in this meta-analysis.For the overall patient population, even though individual trials had negative results, a conservative model was used to derive a slight benefit for PARPi treatment compared to NHA (HR, 0.89; 95% CI, 0.80-0.99)(Figure 3A).Considering the very low heterogeneity of the original study, which became statistically significant after meta-analysis with a larger sample size (Figure S3E).Similar to the findings for rPFS, in the subgroup of patients with HRR gene mutations, PARPi treatment demonstrated improved overall survival (HR, 0.77; 95% CI, 0.64-0.93),while no significant improvements were observed in non-HRR gene-mutated patients (HR, 0.93; 95% CI, 0.78-1.10)(Figure 3B,C).
In the BRCA gene-mutated subgroup, PARPi treatment also showed a therapeutic advantage (HR, 0.62; 95% CI, 0.38-0.99),but the evidence for this advantage in patients without BRCA gene mutations is currently inconclusive (HR, 0.96; 95% CI, 0.83-1.11)(Figure 3D,E).Nevertheless, sensitivity analyses showed heterogeneity in this finding (Figure S3F), possibly due to studies with insufficient OS maturation.This emphasizes the need for more clinical trials to follow up on whether PARPi is effective in improving overall survival in patients without BRCA gene mutations.

Disease Progression and Relief
Based on the comprehensive information disclosed in the included studies, we evaluated four outcomes related to disease progression and relief in the intention-to-treat populations: TFST, TTPP, PSA RR, and ORR.In terms of disease progression, both TFST (HR, 0.72; 95% CI, 0.57-0.89)and TTPP (HR, 0.73; 95% CI, 0.54-0.98)were significantly reduced in the PARPi treatment arm.As for disease relief, PSA RR (OR, 1.52; 95% CI, 1.10-2.10)and ORR (OR, 1.97; 95% CI, 1.27-3.04)also favored the PARPi treatment (Figure S4A-D).Despite substantial heterogeneity among the studies, the consistent conclusions consistently favored the selection of PARPi treatment (Figure S3G-J).

Discussion
In contrast to recent published systematic reviews [25,26], which primarily involve a constrained number of trials, often lacking randomization, potentially leading to incomplete or biased conclusions, this exhaustive meta-analysis, encompassing a corpus of eight meticulously executed prospective randomized controlled trials (RCTs), unequivocally substantiates that the application of poly (ADP-ribose) polymerase (PARP) inhibitors in the therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) confers remarkable enhancements in both overall survival (OS) and radiographic progression-free survival (rPFS) across all patient cohorts.This notable improvement is observed not only among the general population but is especially pronounced in individuals exhibiting BRCA/homologous recombination repair (HRR) mutations.
BRCA1/2, the foremost DNA repair gene loci to be identified, as well as the most widely acknowledged marker for mutation testing concerning the application of PARP inhibitors, have played a pivotal role in this field [27,28].Efforts have also been made to investigate other genes involved in homologous recombination repair (HRR) prior to the initiation of PARP inhibitor treatment, such as ATM, CDK12, CHEK2, and many others [29][30][31].However, a consensus linking specific mutations to the application of PARP inhibitors, apart from BRCA1/2, has yet to be reached.Our findings indicate that patients

Discussion
In contrast to recent published systematic reviews [25,26], which primarily involve a constrained number of trials, often lacking randomization, potentially leading to incomplete or biased conclusions, this exhaustive meta-analysis, encompassing a corpus of eight meticulously executed prospective randomized controlled trials (RCTs), unequivocally substantiates that the application of poly (ADP-ribose) polymerase (PARP) inhibitors in the therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) confers remarkable enhancements in both overall survival (OS) and radiographic progressionfree survival (rPFS) across all patient cohorts.This notable improvement is observed not only among the general population but is especially pronounced in individuals exhibiting BRCA/homologous recombination repair (HRR) mutations.
BRCA1/2, the foremost DNA repair gene loci to be identified, as well as the most widely acknowledged marker for mutation testing concerning the application of PARP inhibitors, have played a pivotal role in this field [27,28].Efforts have also been made to investigate other genes involved in homologous recombination repair (HRR) prior to the initiation of PARP inhibitor treatment, such as ATM, CDK12, CHEK2, and many others [29][30][31].However, a consensus linking specific mutations to the application of PARP inhibitors, apart from BRCA1/2, has yet to be reached.Our findings indicate that patients who tested positive for mutations in the BRCA or HRR genes can derive therapeutic benefits from PARP inhibitor treatment, although some heterogeneity was observed in OS within the subgroup of BRCA-mutated patients.Importantly, the variability in the examination of HRR genes across different trials impairs the efficacy of conclusions establishing the subgroup of patients with HRR mutations as "potentially profited patients".
Even in prostate cancer cases lacking HRR alterations, the combination therapy of PARP inhibitors with androgen receptor inhibitors (ARi) holds great promise due to the synergistic treatment effects observed [32].According to our results, although statistically significant improvements in survival outcomes were not seen in the subgroup of patients without BRCA/HRR mutations, sensitivity analysis pointed towards potential survival benefits for this subgroup upon exclusion of the KEYLYNK-010 study.This finding may be attributed to the use of pembrolizumab in the KEYLYNK-010 study.Similar sensitivity analyses were also conducted for time to prostate-specific antigen radiographic progression (TTPP) and prostate-specific antigen response rate (PSARR), both of which showcased the narrowing impact of PD-1 blockade therapy on the conclusions regarding survival benefits.
It has been postulated that patients without HRR mutations may still derive potential benefits from PARP inhibition [33].On the one hand, PARP inhibitors can attenuate the transcriptional activity of the androgen receptor (AR), thereby enhancing the inhibitory effects of ARi on AR pathways [34,35].On the other hand, AR itself serves as a transcriptional factor that promotes DNA damage response and HRR by facilitating the accumulation of γH2AX and RAD51 foci [36][37][38].Consequently, the obstruction of AR signaling in patients undergoing androgen deprivation therapy (ADT) compromises HRR and leads to compensatory PARP activity.Thus, the inhibition of AR becomes synthetically lethal when combined with PARP inhibition [39,40].Additionally, other yet undiscovered mutation loci may induce sensitivity to PARP inhibition in prostate cancer [41], which may explain why some mCRPC patients lacking deleterious HRR mutations still respond to PARP inhibitors [17].Therefore, further delineation and more detailed studies of the HRR-negative population are warranted, as are additional fundamental research endeavors to uncover new mechanisms and improve the identification of the patient population suitable for PARP inhibitors.
Our comprehensive meta-analysis unequivocally demonstrates the substantial advantages conferred by PARP inhibitors over standard-of-care treatment in the improvement of rPFS and OS among mCRPC patients with any HRR mutation, thereby underscoring the immense therapeutic potential of PARP inhibitors in a stratified manner based on HRR gene-mutation signatures.Nonetheless, while our overall findings in the subgroup of patients without BRCA/HRR mutations do not advocate for the routine application of PARP inhibitors, sensitivity analysis reminds us that further exploration necessitates more profound and comprehensive pre-clinical and clinical evidence.Furthermore, the concept of "patient-centered clinical trials" has gained significant traction in recent times [42].Despite the general responsiveness of BRCA/HRR-positive patients to PARP inhibitors, a subset of these patients fails to derive a survival benefit.The reasons for this subset of patients warrant in-depth subgroup analyses.Collectively, these findings underscore the necessity and significance of molecular testing in guiding patient management and emphasize the importance of establishing treatment frameworks that incorporate precisely targeted therapies for mCRPC patients.
However, it is important to acknowledge a concurrent elevation in the incidence of treatment-emergent adverse events.Regarding safety, the rates of overall adverse events (AEs), grade ≥ 3 AEs, and serious AEs were all higher in the PARP inhibitor treatment arm as compared to the standard-of-care treatment arm.The most frequently observed adverse effects encompassed fatigue, anemia, hypertension, thrombocytopenia, nausea, neutropenia, and others, mirroring the occurrences reported in previous studies involving other solid tumors [6,8].Generally, these side effects can be effectively managed through supportive measures such as transfusion of blood components and growth factor therapy, as well as dose reduction and interruption when necessary.Notably, the incidences of treatment-emergent hypertension were similar irrespective of the utilization of PARP inhibitors, thereby offering an alternative treatment option for individuals who cannot tolerate the elevated blood pressure associated with ARi.

Conclusions
This meta-analysis presents compelling and robust data indicating the favorable clinical efficacy and tolerability of PARP inhibitor (PARPi) treatment, both as a monotherapy and in combination therapy, for the management of refractory metastatic castration-resistant prostate cancer (mCRPC) characterized by BRCA/HRR mutations.To further enhance therapy selection and optimize treatment outcomes, it is imperative to dedicate resources to comprehensively investigate and comprehend predictive markers and signatures associated with treatment response and resistance to PARP inhibitors.This endeavor will enable the development of personalized treatment approaches tailored to individual patients, maximizing therapeutic benefit.

Figure 1 .
Figure 1.The PRISMA flow chart, detailing the article selection process.Figure 1.The PRISMA flow chart, detailing the article selection process.

Figure 1 .
Figure 1.The PRISMA flow chart, detailing the article selection process.Figure 1.The PRISMA flow chart, detailing the article selection process.

:
Risk of bias summary of the included studies; Figure S2: Risk of bias graph of the included studies; Figure S3: Forest plots showing the sensitivity analysis of treatment efficacy in mCRPC patients by sequential omitting each included study, (A) rPFS based on intention-to-treat patients, (B) rPFS based on Non-HRR mutated patients, (C) rPFS based on BRCA mutated patients, (D) rPFS based on Non-BRCA mutated patients, (E) OS based on intention-to-treat patients, (F) OS based on BRCA mutated patients, (G) TFST based on intention-to-treat patients, (H) TTPP based on intention-to-treat patients, (I) PSA RR based on intention-to-treat patients, and (J) ORR based on intention-to-treat patients; Figure S4: Forest plots showing the association of treatment efficacy in mCRPC patients, (A) TFST, (B) TTPP, (C) PSA RR, and (D) ORR; Figure S5: Forest plots showing the association of adverse events with a high incidence rate in mCRPC patients, (A) All grades of anemia, (B) Grade ≥ 3 of anemia, (C) All grades of fatigue, (D) Grade ≥ 3 of fatigue, (E) All grades of hypertension, (F) Grade ≥ 3 of hypertension, (G) All grades of thrombocytopenia, (H) Grade ≥ 3 of thrombocytopenia, (I) All grades of neutropenia, (J) Grade ≥ 3 of neutropenia, (K) All grades of leukopenia, and (L) Grade ≥ 3 of leukopenia; Table S1: Meta-analysis of the primary efficacy and safety of PAPRi for the treatment of mCRPC.Author Contributions: Conceptualization: Z.W. (Zhihua Wang); data curation: L.L., Y.J., Y.T. and X.G.; formal analysis: Z.C., Y.T., X.H. and C.Z.; methodology: L.L. and Y.J.; software: Z.W. (Zefeng Wang); statistical analysis: Z.C. and Z.W. (Zefeng Wang); validation: Y.W., W.Y. and F.C.; visualization: Z.C. and Z.W. (Zefeng Wang); writing-original draft: Z.C. and L.L.; writing-review and editing: Z.W. (Zefeng Wang), F.C. and Z.W. (Zhihua Wang); supervision: Z.W. (Zhihua Wang).All authors have read and agreed to the published version of the manuscript.Funding: This research received no external funding.

Table 1 .
Characteristics of the studies included.

Table 2 .
Characteristics of the patients included.* Patients with bone disease only.